Benzothiepine ileal bile acid transport inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) wherein variable groups are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described

This invention relates to benzothiepine derivatives, or pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof. These benzothiepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.

It is well-known that hyperlipidaemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930–1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134–46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269–74) involved the treatment with substances with an IBAT inhibitory effect.

Re-absorption of bile acid from the gastrointestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of IBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255–287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions. Compounds possessing such IBAT inhibitory activity have been described, see for instance hypolipidaemic the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.

A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.

The present invention is based on the discovery that certain benzothiepine compounds surprisingly inhibit IBAT. Such properties are expected to be of value in the treatment of disease states associated with hyperlipidaemic conditions.

Accordingly, the present invention provides a compound of formula (I):

wherein:

One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyl and the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵ may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ is optionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is a group of formula (IB):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—, —O—, and —S(O)a-; wherein a is 0–2 and R^(n) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independently optionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH) or —P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selected from C₁₋₆alkyl; or R¹⁵ is a group of formula (IC):

wherein:

R²⁴ is selected from hydrogen or C₁₋₄alkyl;

R²⁵ is selected from hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl or R²⁷; wherein said C₁₋₄alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R²⁸;

R²⁶ is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, —P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

z is 0–3; wherein the values of R²⁵ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may be independently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁷ and R²⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, Sulphino, amidino, (C₁₋₄alkyl)₃silyl, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or —P(O)(OR^(a))R^(b)), wherein R^(a) and R^(b) are independently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may be independently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of the present invention there is provided a compound of formula (I):

wherein:

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the other is selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵ may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ is optionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is a group of formula (IB):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—, —O—, and —S(O)a-; wherein a is 0–2 and R^(n) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independently optionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ maybe the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ maybe the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may be independently optionally substituted on carbon by one or more R²¹;

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may be independently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

In this specification the term “alkyl” includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. For example, “C₁₋₆alkyl” includes C₁₋₄alkyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight chained version only and references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only. A similar convention applies to other radicals, for example “phenylC₁₋₆alkyl” would include phenylC₁₋₆alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term “halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. “Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked. Preferably “heteroaryl” refers to a totally unsaturated, monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked. Examples and suitable values of the term “heteroaryl” are thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably the term “heteroaryl” refers to thienyl or indolyl.

“Aryl” is a totally unsaturated, mono or bicyclic carbon ring that contains 3–12 atoms. Preferably “aryl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.

A “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3–12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ring sulphur atom may be optionally oxidised to form the S-oxides. Preferably a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ring sulphur atom may be optionally oxidised to form S-oxide(s). Examples and suitable values of the term “heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3–12 atoms; wherein a —CH₂— group can optionally be replaced by a —C(O)—. Preferably “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.

An example of “C₁₋₆alkanoyloxy” and “C₁₋₄alkanoyloxy” is acetoxy. Examples of “C₁₋₆alkoxycarbonyl” and “C₁₋₄alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₆alkoxy” and “C ₁₋₄alkoxy” include methoxy, ethoxy and propoxy. Examples of “C₁₋₆alkanoylamino” and “C₁₋₄alkanoylamino” include formamido, acetamido and propionylamino. Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” and “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₆alkanoyl” and “C₁₋₄alkanoyl” include propionyl and acetyl. Examples of “N-(C₁₋₆alkyl)amino” and “N-(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of “N,N-(C₁₋₆alkyl)₂amino” and “N,N-(C₁₋₄alkyl)₂amino” include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl. Examples of “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of “N-(C₁₋₆alkyl)sulphamoyl” and “N-(C₁₋₄alkyl)sulphamoyl” are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of “N-(C₁₋₆alkyl)₂sulphamoyl” and “N-(C₁₋₄alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of “N-(C₁₋₆alkyl)carbamoyl” and “N-(C₁₋₄alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl. Examples of “N,N-(C₁₋₆alkyl)₂carbamoyl” and “N,N-(C₁₋₄alkyl)₂carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “(C₁₋₄alkyl)₃silyl,” include trimethylsilyl and methyldiethylsilyl.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric, acetate or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I) examples of pro-drugs include in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of the formula (I).

An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, a N-C₁₋₆alkyl or N,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess IBAT inhibitory activity.

The invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess IBAT inhibitory activity.

It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess IBAT inhibitory activity.

Particular values are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

R¹ and R² are C₁₋₄alkyl.

R¹ and R² are butyl.

One of R¹ and R² is ethyl and the other is butyl.

One of R¹ and R² is ethyl and the other is butyl or R¹ and R² are both butyl.

One of R^(x) and R^(y) is hydrogen and the other is hydroxy.

v is 0 or 1.

v is 0.

R^(z) is C₁₋₄alkyl.

R³ and R⁶ are hydrogen.

R⁴ is methylthio.

R⁴ is hydrogen.

R⁴ is a group of formula (IA) (as depicted above) wherein:

X is —S—;

Ring A is phenyl;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is a group of formula (IB) (as depicted above) wherein:

R¹² is hydrogen;

p is 1 or 2;

R¹³ is hydrogen;

q is 0;

r is 0; and

R¹⁵ is carboxy or sulpho.

R⁴ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio or N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio.

R⁴ is a group of formula (IA) (as depicted above) wherein:

X is —S—;

Ring A is phenyl or thienyl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy or a group of formula (IB) (as depicted above) wherein:

R¹² is hydrogen;

p is 1 or 2;

R¹³ is hydrogen;

q is 0;

r is 0;

R¹⁵ is carboxy or sulpho; and

R¹⁷ is hydroxy or fluoro.

R⁴ is a group of formula (IA) (as depicted above) wherein:

X is —S—;

Ring A is phenyl, 4-hydroxyphenyl, 2-fluorophenyl or thien-2-yl;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy or a group of formula (IB) (as depicted above) wherein:

R¹² is hydrogen;

p is 1 or 2;

R¹³ is hydrogen;

q is 0;

r is 0; and

R¹⁵ is carboxy or sulpho.

R⁴ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio; N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio; {N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}; or {N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}.

R⁵ is hydrogen.

R⁵ is a group of formula (IA).

Therefore in another aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ and R² are C₁₋₄alkyl;

One of R^(x) and R^(y) is hydrogen and the other is hydroxy;

v is 0;

R³ and R⁶ are hydrogen;

R⁴ is a group of formula (IA) (as depicted above) wherein:

X is —S—;

Ring A is phenyl or thienyl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy or a group of formula (IB) (as depicted above) wherein:

R¹² is hydrogen;

p is 1 or 2;

R¹³ is hydrogen;

q is 0;

r is 0;

R¹⁵ is carboxy or sulpho;

R¹⁷ is hydroxy or fluoro; and

R⁵ is hydrogen;

or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in another aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

One of R¹ and R² is ethyl and the other is butyl;

One of R^(x) and R^(y) is hydrogen and the other is hydroxy;

v is 0;

R³ and R⁶ are hydrogen;

R⁴ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio; N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio; {N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}; or {N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}; and

R⁵ is hydrogen;

or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

In another aspect of the invention, preferred compounds of the invention are any one of the examples or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Preferred aspects of the invention are those which relate to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of:

-   Process 1): oxidising a benzothiepine of formula (II):

-   Process 2): for compounds of formula (I) wherein X is —O—,—NR^(a) or     —S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group;

-   Process 3): reacting an acid of formula (Va) or (Vb):

or an activated derivative thereof; with an amine of formula (VI):

-   Process 4): for compounds of formula (I) wherein R¹¹ is a group of     formula (IB); reacting a compound of formula (I) wherein R¹¹ is     carboxy with an amine of formula (VII):

-   Process 5): for compounds of formula (I) wherein R¹¹ is a group of     formula (IB) and R¹⁵ is a group of formula (IC) reacting a compound     of formula (I) wherein R¹⁵ is carboxy with an amine of formula     (VII):

-   Process 6) for compounds of formula (I) wherein one of R⁴ and R⁵ are     independently selected from C₁₋₆alkylthio optionally substituted on     carbon by one or more R¹⁶; reacting a compound of formula (IXa) or     (IXb):

wherein L is a displaceable group; with a thiol of formula (X): R^(m)—H  (X) wherein R^(m) is C₁₋₆alkylthio optionally substituted on carbon by one or more R¹⁶;

-   Process 7): for compounds of formula (I) wherein R¹¹ is carboxy;     deprotecting a compound of formula (XIa):

wherein R^(p) is together with the —OC(O)— group to which it is attached forms an ester;

-   Process 8): for compounds of formula (I) wherein R¹¹ is a group of     formula (IB) and R¹⁵ is carboxy; deprotecting a compound of formula     (XIIa):

wherein R^(p) together with the —OC(O)— group to which it is attached forms an ester;

-   Process 9): for compounds of formula (I) wherein R¹¹ is a group of     formula (IB) and Y is —N(R^(n))C(O)—; reacting an acid of formula     (XIIa):

or an activated derivative thereof; with an amine of formula (XIV):

-   Process 10): for compounds of formula (I) wherein R¹¹ is a group of     formula (IB), R¹⁵ is a group of formula (IC) ad R²⁶ is carboxy;     deprotecting a compound of formula (XVa):

wherein R^(p) together with the —OC(O)— group to which it is attached forms an ester; or Process 11) for compounds of formula (I) wherein one of Rx and Ry is hydroxy and the other is hydrogen; hydrogenating an epoxide of formula (XVI):

and thereafter if necessary or desirable:

-   i) converting a compound of the formula (I) into another compound of     the formula (I); -   ii) removing any protecting groups; -   iii) forming a pharmaceutically acceptable salt, solvate, solvate of     such a salt or a prodrug.

L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.

R^(p) together with the —OC(O)— group to which it is attached forms an ester. Preferably R^(p) is methyl or ethyl. More preferably R^(p) is methyl. In another aspect of the invention R^(p) is C₁₋₆alkyl or phenylC₁₋₆alkyl, preferably C₁₋₄alkyl or benzyl, more preferably t-butyl, methyl, ethyl or benzyl.

Specific reaction conditions for the above reactions are as follows.

-   Process 1): Benzothiepines of formula (II) may be oxidised under     standard sulphur oxidation conditions; for example using hydrogen     peroxide and trifluoroacetic acid at a temperature in the range of     0° C. to reflux, preferably at or near room temperature.

Compounds of formula (II) may be prepared according to Scheme I:

Compounds of formula (IIa) and (IId) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

-   Process 2): Compounds of formula (IIIa) or (IIIb) may be reacted     with compounds of formula (IV) in the presence of a base for example     an inorganic base such as sodium carbonate, or an organic base such     as Hunigs base, in the presence of a suitable solvent such as     acetonitrile, dichloromethane or tetrahydrofuran at a temperature in     the range of 0° C. to reflux, preferably at or near reflux.

Compounds of formula (IIIa) or (IIIb) may be prepared in a similar manner to compounds of formula (II) (but wherein R⁴ or R⁵ is —OH, —NH(R^(a)) or —SH followed by the oxidation step of Process 1). In addition compounds of formula (IIIa) or (IIIb) wherein X is —O— or NR^(a) may prepared by the procedure of WO 96/08484 or WO 98/40375.

Compounds of formula (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

-   Process 3) and Process 4) and Process 5) and Process 9): Acids and     amines may be coupled together in the presence of a suitable     coupling reagent. Standard peptide coupling reagents known in the     art can be employed as suitable coupling reagents, or for example     carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the     presence of a catalyst such as dimethylaminopyridine or     4-pyrrolidinopyridine, optionally in the presence of a base for     example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as     2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include     dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and     dimethylformamide. The coupling reaction may conveniently be     performed at a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of −40 to 40° C.

Compounds of formula (Va) or (Vb) wherein X═—O—,—NR^(a),—S— may be prepared according to Scheme 2:

Wherein L in (IXa) and (IXb) is a displaceable group e.g. bromo, chloro, fluoro, mesyl or tosyl and wherein X is —O—,—S—, NR^(a) (optionally for —SO— and —SO₂— followed by the oxidation step of Process 1).

Compounds of formula (Va) and (Vb) where X is —SO— or —SO₂— may be prepared by oxidising the resulting compounds of formula (Va) and (Vb) from Scheme 2 where X is —S—.

Compounds of formula (Va) or (Vb) wherein X is —CH₂—, and n is 1, may be prepared according to Scheme 3.

The skilled person will appreciate that the above reaction scheme may be manipulated to prepare compounds of formula (Va) or (Vb) where n is 2 or 3.

Compounds of formula (XIIIa) or (XIIIb) may be prepared by manipulations known to the skilled person of the processes described herein.

Compounds of formula (Vc), (VI), (VII), (VIII) and (XIV) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

-   Process 6): Compounds of formula (IXa) and (IXb) may be reacted with     thiols of formula (X) in the presence of base, for example an     inorganic base such as sodium carbonate or an organic base such as     Hunigs base, in the presence of a suitable solvent such as DMF or     THF at a temperature in the range of 0° C. to reflux.

Compounds of formula (IXa) and (IXb) may be prepared by any of the procedures above for the preparation of compounds of formula (I), but wherein one of R⁴ and R⁵ is L.

Compounds of formula (X) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

-   Process 7) and Process 8) and Process 10): Esters of formula (XIa),     (XIb), (XIIa), (XIIb), (XVa) and (XVb) may be deprotected under     standard conditions such as those described below, for example they     may be deprotected with sodium hydroxide in methanol at room     temperature.

Esters of formula (XIa), (XIb), (XIa), (XIIb), (XVa) and (XVb) may be prepared by any of the procedures above for the preparation of compounds of formula (I), but wherein R¹¹ or R¹⁵ or R²⁶ is an ester.

-   Process 11) Compounds of formula (XVI) may be hydrogenated under     standard conditions such as in the presence of a palladium catalyst.

Compounds of formula (XVI) may be prepared by reacting compounds of formula (IIf) with excess m-chloroperoxybenzoic acid.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present invention possess IBAT inhibitory activity. These properties may be assessed, for example, using an in vitro test assay for studying the effect on bile acid uptake in IBAT-transfected cells (Smith L., Price-Jones M. J., Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227–230) or in vivo by studying the effect on radiolabelled bile acid absorption in mice/rats (Lewis M. C., Brieaddy L. E. and Root C., J., J Lip Res 1995, 36, 1098–1105).

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventional manner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, will normally be administered to a warm-blooded animal at a unit dose within the range 5–5000 mg per square meter body area of the animal, i.e. approximately 0.02–100 mg/kg, preferably 0.02–50 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1–250 mg of active ingredient. Preferably a daily dose in the range of 1–50 mg/kg, particularly 0.1–10 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

According to a further aspect of the present invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, are effective IBAT inhibitors, and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions.

Thus according to this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore, in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore, in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

Herein, where “the production of an IBAT inhibitory effect” or “producing an IBAT inhibitory effect” is referred to particularly this refers to the treatment of hyperlipidaemic conditions. In another aspect, “the production of an IBAT inhibitory effect” or “producing an IBAT inhibitory effect” refers to the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In another aspect “the production of an IBAT inhibitory effect” or “producing an IBAT inhibitory effect” refers to the treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks. In another aspect “the production of an IBAT inhibitory effect” or “producing an IBAT inhibitory effect” refers to the treatment of atherosclerosis, coronary heart diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, stroke and transient ischaemic attacks in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

The size of the dose required for the therapeutic or prophylactic treatment will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 0.1–50 mg/kg preferably 0.1–10 mg/kg is envisaged.

The IBAT inhibitory activity defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. According to this aspect of the invention there is provided a pharmaceutical product comprising a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore and an additional IBAT inhibitory substance as defined hereinbefore and an additional hypolipidaemic agent for the conjoint treatment of hyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, may be administered in association with an HMG Co-A reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductase inhibitors, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are statins well known in the art. Particular statins are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin, mevastatin and (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more particular statin is atorvastatin calcium salt. A further particular statin is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more particular statin is rosuvastatin calcium salt.

In an additional aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof may be administered in association with an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and/or a bile acid binder thereby avoiding a possible risk of excess of bile acids in colon caused by the inhibition of the ileal bile acid transport system. An excess of bile acids in the visceral contents may cause diarrhoea. Thus, the present invention also provides a treatment of a possible side effect such as diarrhoea in patients during therapy comprising the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof will by its action decrease the endogenous cholesterol available for the bile acid synthesis and have an additive effect in combination with the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof on lipid lowering.

Suitable bile acid binders for such a combination therapy are resins, such as cholestyramine and cholestipol. One advantage is that the dose of bile acid binder might be kept lower than the therapeutic dose for treatment of cholesterolaemia in single treatment comprising solely a bile acid binder. By a low dose of bile acid binder any possible side effects caused by poor tolerance of the patient to the therapeutic dose could also be avoided.

Therefore in an additional feature of the invention, there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with a bile acid binder.

Therefore in an additional feature of the invention, there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in simultaneous, sequential or separate administration with a bile acid binder.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a bile acid binder.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in simultaneous, sequential or separate administration with a bile acid binder.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof and a bile acid binder.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, in a first     unit dosage form; -   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable     salt, solvate, solvate of such a salt or a prodrug thereof; in a     second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, in a first     unit dosage form; -   b) a bile acid binder; in a second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, in a first     unit dosage form; -   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable     salt, solvate, solvate of such a salt or a prodrug thereof; in a     second unit dosage form; -   c) a bile acid binder; in a third unit dosage form; and -   d) container means for containing said first, second and third     dosage forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, together with     a pharmaceutically acceptable diluent or carrier, in a first unit     dosage form; -   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable     salt, solvate, solvate of such a salt or a prodrug thereof, in a     second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, together with     a pharmaceutically acceptable diluent or carrier, in a first unit     dosage form; -   b) a bile acid binder, in a second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, together with     a pharmaceutically acceptable diluent or carrier, in a first unit     dosage form; -   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable     salt, solvate, solvate of such a salt or a prodrug thereof, in a     second unit dosage form; and -   c) a bile acid binder; in a third unit dosage form; and -   d) container means for containing said first, second and third     dosage forms.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, a bile acid binder, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of a bile acid binder, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable excipient, with the simultaneous, sequential or separate administration of an effective amount of a bile acid binder, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from:

-   -   a CETP (cholesteryl ester transfer protein) inhibitor, for         example those referenced and described in WO 00/38725 page 7         line 22-page 10, line 17 which are incorporated herein by         reference;     -   a cholesterol absorption antagonist for example azetidinones         such as SCH 58235 and those described in U.S. Pat. No. 5,767,115         which are incorporated herein by reference;     -   a MTP (microsomal transfer protein) inhibitor for example those         described in Science, 282, 751–54, 1998 which are incorporated         herein by reference;     -   a fibric acid derivative; for example clofibrate, gemfibrozil,         fenofibrate, ciprofibrate and bezafibrate;     -   a nicotinic acid derivative, for example, nicotinic acid         (niacin), acipimox and niceritrol;     -   a phytosterol compound for example stanols;     -   probucol;     -   an anti-obesity compound for example orlistat (EP 129,748) and         sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);     -   an antihypertensive compound for example an angiotensin         converting enzyme inhibitor, an angiotensin II receptor         antagonist, an andrenergic blocker, an alpha andrenergic         blocker, a beta andrenergic blocker, a mixed alpha/beta         andrenergic blocker, an andrenergic stimulant, calcium channel         blocker, a diuretic or a vasodilator;     -   insulin;     -   sulphonylureas including glibenclamide, tolbutamide;     -   metformin; and/or     -   acarbose;         or a pharmaceutically acceptable salt, solvate, solvate of such         a salt or a prodrug thereof, optionally together with a         pharmaceutically acceptable diluent or carrier to a warm-blooded         animal, such as man in need of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof, including active metabolites, which can be used in combination with a compound of formula (I) include but are not limited to, the following compounds: alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for uses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof for use in combination with a compound of formula (I) include, but are not limited to, compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, teimisartan and eprosartan. Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.

In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, may be administered in association with a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623–634 (in particular the compounds described in the patent applications listed on page 634) and J Med Chem, 2000, 43, 527 which are all incorporated herein by reference. Particularly a PPAR alpha and/or gamma agonist refers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041, NN622/Ragaglitazar, BMS 298585and GW 2433. Particularly a PPAR alpha and/or gamma agonist refers to (S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid and pharmaceutically acceptable salts thereof.

Therefore in an additional feature of the invention, there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, in a first     unit dosage form; -   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically     acceptable salt, solvate, solvate of such a salt or a prodrug     thereof; in a second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,     solvate, solvate of such a salt or a prodrug thereof, together with     a pharmaceutically acceptable diluent or carrier, in a first unit     dosage form; -   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically     acceptable salt, solvate, solvate of such a salt or a prodrug     thereof, in a second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

In addition to their use in therapeutic medicine, the compounds of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of IBAT in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

Many of the intermediates described herein are novel and are thus provided as a further feature of the invention. For Example compounds of formula (XIa), (IXb), (XIIa), (XIIb), (XVa) and (XVb) show IBAT inhibitory activity when tested in the above referenced in vitro test assay and are thus claimed as a further feature of the invention.

Thus in a further feature of the invention, there is provided a compound of formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.

According to an additional aspect of the present invention there is provided a compound of the formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.

Thus according to this aspect of the invention there is provided a compound of the formula (XIa), (XIb), (XIIa), (XIIb)), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the use of a compound of the formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof as defined hereinbefore in the manufacture of a medicament for use in the production of an IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula (XIa), (XIb), (XIIa), (XIIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof as defined hereinbefore in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there is provided a method for producing an IBAT inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

EXAMPLES

The invention will now be illustrated in the following non limiting examples, in which standard techniques known to the skilled chemist and techniques analogous to those described in these examples may be used where appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and     work up procedures were carried out after removal of residual solids     such as drying agents by filtration; -   (ii) all reactions were carried out under an inert atmosphere at     ambient temperature, typically in the range 18–25° C., with solvents     of HPLC grade under anhydrous conditions, unless otherwise stated; -   (iii) column chromatography (by the flash procedure) was performed     on Silica gel 40–63 μm Merck); -   (iv) yields are given for illustration only and are not necessarily     the maximum attainable; -   (v) the structures of the end products of the formula (I) were     generally confirmed by nuclear (generally proton) magnetic resonance     (NMR) and mass spectral techniques; magnetic resonance chemical     shift values were measured in deuterated CD₃OD (unless otherwise     stated) on the delta scale (ppm downfield from tetramethylsilane);     proton data is quoted unless otherwise stated; spectra were recorded     on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity     plus-600 MHz or on Varian Inova-500 MHz spectrometer; and peak     multiplicities are shown as follows: s, singlet; d, doublet; dd,     double doublet; t, triplet; tt, triple triplet; q, quartet; tq,     triple quartet; m, multiplet; br, broad; LCMS were recorded on a     Waters ZMD, LC column xTerra MS C₈(Waters), detection with a HP 1100     MS-detector diode array equipped; mass spectra (MS) (loop) were     recorded on VG Platform II (Fisons Instruments) with a HP-1100     MS-detector diode array equipped; unless otherwise stated the mass     ion quoted is (MH⁺), -   (vi) unless further details are specified in the text, analytical     high performance liquid chromatography (HPLC) was performed on Prep     LC 2000 (Waters), Kromasil C₈, 7 μm, (Akzo Nobel); MeCN and     de-ionised water 100 mM ammonium acetate as mobile phases, with     suitable composition; -   (vii) intermediates were not generally fully characterised and     purity was assessed by thin layer chromatography (TLC), HPLC,     infra-red (IR), MS or NMR analysis; -   (viii) where solutions were dried sodium sulphate was the drying     agent; -   (ix) where an “ISOLUTE” column is referred to, this means a column     containing 2 g of silica, the silica being contained in a 6 ml     disposable syringe and supported by a porous disc of 54 Å pore size,     obtained from International Sorbent Technology under the name     “ISOLUTE”; “ISOLUTE” is a registered trade mark; -   (x) the following abbreviations may be used hereinbefore or     hereinafter:     -   DCM dichloromethane;     -   DMF N,N-dimethylformamide;     -   TBTU o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium         tetrafluoroborate;     -   EtOAc ethyl acetate; and     -   MeCN acetonitrile.

Example 1 1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5- phenyl-7-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine

1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(carboxymethylthio)-2,3,4,5-tetrahydrobenzothiepine Method 3; 40 mg, 0.086 mmol), (R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 2; 31 mg, 0.117 mmol) and TBTU (45 mg, 0.140 mmol) were dissolved in DCM (2.5 ml) and 2,6-lutidine (0.03 ml, 0.243 mmol) was added. After stirring at room temperature for 3 hours the reaction mixture was filtered through a short silica column. The crude ester was dissolved in DCM (5 ml) and trifluoroacetic acid (1 ml) was added. After stirring at room temperature over night, the solvents were evaporated and purification with preparative HPLC using MeCN/ammonium acetate buffer (50:50) gave the title compound (26 mg, 46%). NMR (400 MHz, DMSO-d₆): 0.74 (t, 3H), 0.84 (t, 3H), 1.02 (m, 1H), 1.18–1.46 (m, 5H), 1.60 (m, 1H), 2.01 (m, 1H), 3.08/3.15 (ABq, 2H), 3.56–3.85 (m, 4H), 3.94 (s, 1H), 5.23 (d, 1H), 5.48 (d, 1H), 6.43 (dd, 1H), 7.21–7.44 (m, 11H), 7.73 (dd, 1H), 8.47 (brs, 1 H), 8.82 (m, 1H).

Example 2 1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine Ammonia Sal

1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(carboxymethylthio)-2,3,4,5-tetrahydrobenzothiepine (Method 3; 50 mg, 0.108 mmol), 2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid (Method 4; 35 mg, 0.127 mmol) and TBTU (45 mg, 0.140 mmol) were dissolved in DMF (2 ml) and N-methylmorpholine (0.03 ml, 0.270 mmol) was added. After stirring at ambient temperature for 4 hours the reaction mixture was diluted with MeCN/ammonium acetate buffer (50:50) and purified with preparative HPLC using MeCN/ammonium acetate buffer (50:50) to give the title compound (49 mg, 61%).NMR (400 MHz, DMSO-d₆): 0.74 (t, 3H), 0.84 (t, 3H), 1.02 (m, 1H), 1.18–1.46 (m, 5H), 1.60 (m, 1H), 2.01 (m, 1H), 3.11 (m, 2H), 3.28 (m, 2H), 3.75 (m, 2H), 3.95 (s, 1H), 5.13 (d, 1H), 5.22 (s, 1H), 6.43 (t, 1H), 6.67 (d, 2H), 7.08 (m, 2H), 7.28–7.44 (m, 9H), 7.76 (m, 1H), 8.16 (m, 1H), 8.68 (dd, 1H).

Example 3 1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine

1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(carboxymethylthio)-2,3,4,5-tetrahydrobenzothiepine (Method 3; 59 mg, 0.13 mmol) and methyl amino (2-fluorophenyl)acetate hydrochloride (40 mg, 0.18 mmol) were added to DCM (3.0 ml) and 2,6-lutidine (0.04 ml, 0.38 mmol) was added. The reaction mixture was stirred at ambient temperature for 5 min and TBTU (58 mg, 0.18 mmol) was added. After siring at ambient temperature for 3 hours the reaction mixture was diluted with DCM (5 ml) and was washed with HCl (aq., 1 M, 5 ml). The DCM layer was separated and evaporated to dryness. The residue was dissolved in THF (2.0 ml) and water (1.0 ml) and NaOH (aq., 1 M, 0.30 mmol) was added. After stirring at ambient temperature for 2 hours the reaction mixture was quenched with HCl (aq., 1 M), diluted with water (10 ml) and extracted with DCM (3×5 ml). The combined organic layers were purified with preparative HPLC MeCN/ammonium acetate buffer 40:60 to give the title compound (70 mg, 89%). NMR (400 MHz, DMSO-d₆): 0.74 (t, 3H), 0.84 (t, 3H), 1.00 (m, 1H), 1.18–1.46 (m, 5H), 1.60 (m, 1H), 2.02 (m, 1H), 3.11 (m, 2H), 3.69 (m, 2H), 3.94 (s, 1H), 5.04 (t, 1H), 5.23 (d, 1H), 6.44 (d, 1H), 6.94–7.44 (m, 11H), 7.70 (t, 1H), 8.40 (m, 1H).

Example 4 1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine

The title compound was synthesized according to the procedure of Example 3 but with methyl amino(thien-2-yl)acetate hydrochloride as starting material. NMR (400 MHz, DMSO-d₆): 0.74 (t, 3H), 0.84 (t, 3H), 1.01 (m, 1H), 1.20–1.47 (m, 5H), 1.60 (m, 1H), 2.01 (m, 1H), 3.12 (m, 2H), 3.73 (m, 2H), 3.95 (s, 1H), 5.03 (m, 1H), 5.24 (s, 1H), 6.45 (m, 1H), 6.75 (m, 1H), 6.81 (m, 1H), 7.20 (m, 1H), 7.33 (m, 3H), 7.41 (m, 4H), 7.75 (dd, 1H), 8.32 (dd, 1H).

Preparation of Starting Materials

The starting materials for the Examples above are either commercially available or are readily prepared by standard Methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions.

Method 1

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine

(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (10 g, 35.0 mmol) and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) was dissolved in DCM (200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 min at 0° C. TBTU (12.4 g, 38.6 mmol) was added and stirring was continued for 1.5 hours at 0° C. and 3.75 hours at room temperature. The reaction mixture was washed with water (2×100 ml), dried (MgSO₄) and purified with flash chromatography (DCM:EtOAc 7:1→5:1) to give the title compound (13 g, 94%). NMR (500 MHz, CDCl₃): 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd, 1H), 5.10 (m, 2H), 5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H), 7.30–7.44 (m, 10H).

Method 2

(R)-α-[N-(t-Butoxycarbonylmethyl)carbamoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 1; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) and toluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation was performed at atmospheric pressure for 5.5 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and the solvents were evaporated to give the title compound (8.4 g, 99%). NMR (600 MHz, CDCl₃): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31–7.42 (m, 5H), 7.51 (brs, 1H).

Method 3

1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5- phenyl-7-(carboxymethylthio)-2,3,4,5-tetrahydrobenzothiepi

1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-fluoro-2,3,4,5-tetrahydrobenzothiepine (prepared according to WO 98/40375; 300 mg, 0.77 mmol) was dissolved in DMF (3 ml) and caesium carbonate (540 mg, 1.66 mmol) was added followed by ethyl thioglycolate (0.17 ml, 1.54 mmol) and the reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 100° C. for 5 min. The reaction mixture was added to water (25 ml), extracted with DCM (5×5 ml) and concentrated. The crude ethyl ester was dissolved in THF (4 ml) and water (2 ml) and NaOH (1 M, 4 ml) was added. The reaction mixture was stirred at ambient temperature for 6 hours, quenched with HCl (1 M), diluted with water (25 ml) and extracted with DCM (4×5 ml). The combined organic layers were purified with preparative HPLC using MeCN/ammonium acetate buffer as the eluent (50:50) to give the title compound (172 mg, 48%). NMR (400 MHz, DMSO-d₆): 0.74 (t, 3H), 0.84 (t, 3H), 1.01 (m, 1H), 1.18–1.46 (m, 5H), 1.60 (m, 1H), 2.02 (m, 1H), 3.07/3.12 (ABq, 2H), 3.33/3.39 (ABq, 2H), 3.95 (s, 1H), 5.23 (s, 1H), 6.38 (d, 1H), 7.19 (dd, 1H), 7.34 (m, 1H), 7.42 (m, 4H), 7.73 (d, 1H).

Method 4

2-{[(2R)-2-Amino-2-(4-hydroxy phenyl)ethanoyl]amino}ethanesulphonic Acid

N-Boc-4-hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved in DMF (5 ml) and tetrabutylammonium taurine (2.36 g, 6.42 mmol) was added together with additionally 5 ml DMF. The resulting suspension was cooled on ice and TBTU (1.24 g, 3.85 mmol) was added. The ice bath was removed after 30 min and the mixture was stirred for 2 hours before it was filtered and concentrated. TFA in DCM (20%, 20 ml) was added and the reaction mixture was stirred over night. Ethanol (20 ml) was added and the solvents evaporated. The crude product was refluxed in ethanol (100 ml) for 1 hour. Filtration yielded the pure title compound as a white solid, 626 mg (71%). NMR DMSO-d₆): 2.4–2.6 (m, 2H),3.2–3.4 (m, 2H),4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t, 1H), 8.4 (brs, 3H), 9.7 (s, 1H). 

1. A compound of formula (I):

wherein: One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyl and the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl; R^(x) and R^(y) are independently selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2; R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆aIkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl and N,N-(C₁₋₆alkyl)₂sulphamoyl; v is 0–5; one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵ may be optionally substituted on carbon by one or more R¹⁶; X is —O—, —N(R^(a))—, —S(O)_(b)—or —CH(R^(a))—; wherein R^(a) is hydrogen or C₁₋₆alkyl and b is 0–2; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷; R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ is optionally substituted by one or more substituents selected from R¹⁸; R⁸ is hydrogen or C₁₋₄alkyl; R⁹ is hydrogen or C₁₋₄alkyl; R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionally substituted by one or more substituents selected from R¹⁹; R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is a group of formula (IB):

wherein: Y is —N(R^(n))—, —N(R^(n))C(O)—, —O—, and —S(O)a-; wherein a is 0–2 and R^(n) is hydrogen or C₁₋₄alkyl; R¹² is hydrogen or C₁₋₄alkyl; R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independently optionally substituted by one or more substituents selected from R²⁰; R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selected from C₁₋₆alkyl; or R¹⁵ is a group of formula (IC):

wherein: R²⁴ is selected from hydrogen or C₁₋₄alkyl; R²⁵ is selected from hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl or R²⁷; wherein said C₁₋₄alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R²⁸; R²⁶ is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, —P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selected from C₁₋₆alkyl; p is 1–3; wherein the values of R¹³ may be the same or different; q is 0–1; r is 0–3; wherein the values of R¹⁴ may be the same or different; m is 0–2; wherein the values of R¹⁰ may be the same or different; n is 1–3; wherein the values of R⁷ may be the same or different; z is 0–3; wherein the values of R²⁵ may be the same or different; R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄ alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl and N,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may be independently optionally substituted on carbon by one or more R²¹; R¹⁹, R²⁰, R²⁷ and R²⁸ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄ alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄ alkyl)₂carbamoyl, C₁₋₄ alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, (C₁₋₄alkyl)₃silyl, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may be independently optionally substituted on carbon by one or more R²²; R²¹ and R²² are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 2. A compound of formula (I) as claimed in claim 1 wherein one of R¹ and R² is ethyl and the other is butyl or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 3. A compound of formula (I) as claimed in claim 1 wherein one of R^(x) and R^(y) is hydrogen and the other is hydroxy or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 4. A compound of formula (I) as claimed in claim 1 wherein v is 0 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 5. A compound of formula (I) as claimed in claim 1 wherein R³ and R⁶ are hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 6. A compound of formula (I) as claimed in claim 1 wherein R⁴ is a group of formula (IA) wherein: X is —S—; Ring A is phenyl or thienyl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷; n is 1; R⁷ is hydrogen; R⁸ is hydrogen; R⁹ is hydrogen; m is 0; R¹¹ is carboxy or a group of formula (IB) wherein: R¹² is hydrogen; p is 1 or 2; R¹³ is hydrogen; q is 0; r is 0; R¹⁵ is carboxy or sulpho; and R¹⁷ is hydroxy or fluoro; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 7. A compound of formula (I) as claimed in claim 1 wherein R⁵ is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 8. A compound of formula (I) as claimed in claim 1 wherein: R¹ and R² are C₁₋₄alkyl; One of R^(x) and R^(y) is hydrogen and the other is hydroxy; v is 0; R³ and R⁶ are hydrogen; R⁴ is a group of formula (IA) wherein: X is —S—; Ring A is phenyl or thienyl; wherein Ring A is optionally substituted by one or more substituents selected from R¹⁷; n is 1; R⁷ hydrogen; R⁸ is hydrogen; R⁹ is hydrogen; m is 0; R¹¹ is carboxy or a group of formula (IB) wherein: R¹² hydrogen; p is 1 or 2; R¹³ is hydrogen; q is 0; r is 0; R¹⁵ is carboxy or sulpho; R¹⁷ is hydroxy or fluoro; and R⁵ hydrogen; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 9. A compound of formula (I) as claimed in claim 1, selected from: 1,1 -dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N- {(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine; 1,1 -dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethylthio)-2,3,4,5-tetrahydrobenzothiepine ammonia salt; 1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[α-(carboxy)-2-fluorobenzyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine; and 1,1-dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-{N-[1-(carboxy)-1-(thien-2-yl)methyl]carbamoylmethylthio}-2,3,4,5-tetrahydrobenzothiepine; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 10. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in claim 1, which process comprises of: Process 1): oxidising a benzothiepine of formula (II):

Process 2): for compounds of formula (I) wherein X is —O—, —NR^(a) or —S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group; Process 3): reacting an acid of formula (Va) or (Yb):

or an activated derivative thereof; with an amine of formula (VI):

Process 4): for compounds of formula (I) wherein R¹¹ is a group of formula (IB); reacting a compound of formula (I) wherein R¹¹ is carboxy with an amine of formula (VII):

Process 5): for compounds of formula (I) wherein R¹¹ is a group of formula (IB) and R¹⁵ is a group of formula (IC) reacting a compound of formula (I) wherein R¹⁵ is carboxy with an amine of formula (VIII):

Process 6) for compounds of formula (I) wherein one of R⁴ and R⁵ are independently selected from C₁₋₆alkylthio optionally substituted on carbon by one or more R¹⁶; reacting a compound of formula (IXa) or (IXb):

wherein L is a displaceable group; with a thiol of formula (X): R^(m)—H  (X) wherein R^(m) is C₁₋₆alkylthio optionally substituted on carbon by one or more R¹⁶; Process 7): for compounds of formula (I) wherein R¹¹ is carboxy; deprotecting a compound of formula (XIa):

wherein R^(p) is together with the —OC(O)— group to which it is attached forms an ester; Process 8): for compounds of formula (I) wherein R¹¹ is a group of formula (IB) and R¹⁵ is carboxy; deprotecting a compound of formula (XIIa):

wherein R^(p) together with the —OC(O)— group to which it is attached forms an ester; Process 9): for compounds of formula (I) wherein R¹¹ is a group of formula (IB) and Y is —N(R^(n))C(O)—; reacting an acid of formula (XIIIa):

or an activated derivative thereof; with an amine of formula (XIV):

Process 10): for compounds of formula (I) wherein R¹¹ is a group of formula (IB), R¹⁵ is a group of formula (IC) and R²⁶ is carboxy; deprotecting a compound of formula (XVa):

wherein R^(p) together with the —OC(O)— group to which it is attached forms an ester; or Process 11) for compounds of formula (I) wherein one of Rx and Ry is hydroxy and the other is hydrogen; hydrogenating an epoxide of formula (XVI):

and thereafter optionally: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug.
 11. A method for producing an IBAT inhibitory effect in a warm-blooded animal, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to
 9. 12. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 9, in association with a pharmaceutically-acceptable diluent or carrier.
 13. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 9, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
 14. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 9, and a bile acid binder, in association with a pharmaceutically acceptable diluent or carrier.
 15. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 9, and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a bile acid binder in association with a pharmaceutically acceptable diluent or carrier.
 16. A composition according to claim 13 wherein the HMG Co-A reductase inhibitor is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 17. A composition according to claim 13 wherein the HMG Co-A reductase inhibitor is rosuvastatin, or a pharmaceutically acceptable salt thereof.
 18. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, as claimed in any one of claims 1 to 9 and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
 19. A composition according to claim 18 wherein the PPAR alpha and/or gamma agonist is (S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid or a pharmaceutically acceptable salt thereof.
 20. A composition according to claim 15 wherein the HMG Co-A reductase inhibitor is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
 21. A composition according to claim 15 wherein the HMG Co-A reductase inhibitor is rosuvastatin, or a pharmaceutically acceptable salt thereof. 